Modeling peanut allergy in mice

One of the challenges of understanding food allergies is developing animal models that mirror human food allergies. Here, Zhang et al. have developed a peanut allergy model in mice where feeding mice peanuts alongside immune adjuvant, cholera toxin, promoted the development of peanut-specific antibodies. In addition to peanut-reactive immunoglobulin A (IgA) antibodies, these mice also developed peanut-specific IgE and IgG antibodies. Although development of IgA was independent of T follicular helper (Tfh) cells, Tfh cells were required for the generation of peanut-specific IgE and IgG antibodies. In addition to developing a model to study peanut allergy in mice, their results have also brought to the fore the role of Tfh cells in driving distinct antibody-mediated responses.

Abstract

Immunoglobulin A (IgA) is the dominant antibody isotype in the gut and has been shown to regulate microbiota. Mucosal IgA is also widely believed to prevent food allergens from penetrating the gut lining. Even though recent work has elucidated how bacteria-reactive IgA is induced, little is known about how IgA to food antigens is regulated. Although IgA is presumed to be induced in a healthy gut at steady state via dietary exposure, our data do not support this premise. We found that daily food exposure only induced low-level, cross-reactive IgA in a minority of mice. In contrast, induction of significant levels of peanut-specific IgA strictly required a mucosal adjuvant. Although induction of peanut-specific IgA required T cells and CD40L, it was T follicular helper (TFH) cell, germinal center, and T follicular regulatory (TFR) cell–independent. In contrast, IgG1 and IgE production to peanut required TFH cells. These data suggest an alternative paradigm in which the cellular mechanism of IgA production to food antigens is distinct from IgE and IgG1. We developed an equivalent assay to study this process in stool samples from healthy, nonallergic humans, which revealed substantial levels of peanut-specific IgA that were stable over time. Similar to mice, patients with loss of CD40L function had impaired titers of gut peanut-specific IgA. This work challenges two widely believed but untested paradigms about antibody production to dietary antigens: (i) the steady state/tolerogenic response to food antigens includes IgA production and (ii) TFH cells drive food-specific gut IgA.